Summary of Research: Terminal Complement Inhibitor Ravulizumab in Generalized Myasthenia Gravis.

This article provides a summary of a previously published paper: Terminal Complement Inhibitor Ravulizumab in Generalized Myasthenia Gravis. The paper reported the results of the CHAMPION-MG trial which investigated the drug ravulizumab in the rare disease, myasthenia gravis. Terminal Complement Inhibitor Ravulizumab in Generalized Myasthenia Gravis (MP4 594600 KB).

Developing a Standardized Approach to Grading the Level of Brain Dysfunction on EEG.

PURPOSE: To assess variability in interpretation of electroencephalogram (EEG) background activity and qualitative grading of cerebral dysfunction based on EEG findings, including which EEG features are deemed most important in this determination. METHODS: A web-based survey (Qualtrics) was disseminated to electroencephalographers practicing in institutions participating in the Critical Care EEG Monitoring Research Consortium between May 2017 and August 2018. Respondents answered 12 questions pertaining to their training and EEG interpretation practices and graded 40 EEG segments (15-second epochs depicting patients' most stimulated state) using a 6-grade scale. Fleiss' Kappa statistic evaluated interrater agreement. RESULTS: Of 110 respondents, 78.2% were attending electroencephalographers with a mean of 8.3 years of experience beyond training. Despite 83% supporting the need for a standardized approach to interpreting the degree of dysfunction on EEG, only 13.6% used a previously published or an institutional grading scale. The overall interrater agreement was fair ( k = 0.35). Having Critical Care EEG Monitoring Research Consortium nomenclature certification (40.9%) or EEG board certification (70%) did not improve interrater agreement ( k = 0.26). Predominant awake frequencies and posterior dominant rhythm were ranked as the most important variables in grading background dysfunction, followed by continuity and reactivity. CONCLUSIONS: Despite the preference for a standardized grading scale for background EEG interpretation, the lack of interrater agreement on levels of dysfunction even among experienced academic electroencephalographers unveils a barrier to the widespread use of EEG as a clinical and research neuromonitoring tool. There was reasonable agreement on the features that are most important in this determination. A standardized approach to grading cerebral dysfunction, currently used by the authors, and based on this work, is proposed.

Terminal Complement Inhibitor Ravulizumab in Generalized Myasthenia Gravis.

BACKGROUND: Generalized myasthenia gravis (gMG) is a rare, chronic, and debilitating autoimmune disease. Activation of the complement system by autoantibodies against the postsynaptic acetylcholine receptor (AChR) leads to destruction of the postsynaptic membrane and disruption of neuromuscular transmission. This trial evaluated ravulizumab, a long-acting inhibitor of terminal complement protein C5, as a treatment for gMG. METHODS: In this randomized, double-blind, placebo-controlled, multinational trial, we randomly assigned (1:1) patients with anti-AChR antibody-positive gMG to intravenous ravulizumab or placebo for 26 weeks. Patients received a loading dose on day 1, followed by maintenance doses on day 15 and every 8 weeks thereafter. The primary end point and first secondary end point (change from baseline to week 26 in patient-reported Myasthenia Gravis­Activities of Daily Living [MG-ADL] scale and clinician-reported Quantitative Myasthenia Gravis [QMG] total scores, respectively) were compared between the ravulizumab- and placebo-treated groups. RESULTS: In total, 175 patients were enrolled. Ravulizumab significantly increased the magnitude of mean changes from baseline to week 26 versus placebo in MG-ADL (−3.1 vs. −1.4; P<0.001) and QMG (−2.8 vs. −0.8; P<0.001) total scores. Improvements in both measures occurred within 1 week of ravulizumab initiation and were sustained through week 26. QMG total scores improved by 5 points or more in a significantly greater proportion of ravulizumab-treated patients than of those receiving placebo (30.0% vs. 11.3%; P=0.005). No notable differences in adverse events were observed. CONCLUSIONS: Ravulizumab demonstrated rapid and sustained improvements in both patient- and clinician-reported outcomes and had a side effect and adverse-event profile that did not limit treatment in adults with anti-AChR antibody-positive gMG. (Funded by Alexion, AstraZeneca Rare Disease; ClinicalTrials.gov number, NCT03920293; EudraCT number, 2018-003243-39.)

Bilateral independent periodic discharges are associated with electrographic seizures and poor outcome: A case-control study.

OBJECTIVE: To determine the clinical correlates bilateral independent periodic discharges (BIPDs) and their association with electrographic seizures and outcome. METHODS: Retrospective case-control study of patients with BIPDs compared to patients without periodic discharges ("No PDs") and patients with lateralized periodic discharges ("LPDs"), matched for age, etiology and level of alertness. RESULTS: We included 85 cases and 85 controls in each group. The most frequent etiologies of BIPDs were stroke, CNS infections, and anoxic brain injury. Acute bilateral cerebral injury was more common in the BIPDs group than in the No PDs and LPDs groups (70% vs. 37% vs. 35%). Electrographic seizures were more common with BIPDs than in the absence of PDs (45% vs. 8%), but not than with LPDs (52%). Mortality was higher in the BIPDs group (36%) than in the No PDs group (18%), with fewer patients with BIPDs achieving good outcome (moderate disability or better; 18% vs. 36%), but not than in the LPDs group (24% mortality, 26% good outcome). In multivariate analyses, BIPDs remained associated with mortality (OR: 3.0 [1.4-6.4]) and poor outcome (OR: 2.9 [1.4-6.2]). CONCLUSION: BIPDs are caused by bilateral acute brain injury and are associated with a high risk of electrographic seizures and of poor outcome. SIGNIFICANCE: BIPDs are uncommon but their identification in critically ill patients has potential important implications, both in terms of clinical management and prognostication.

Clinical Correlates of Periodic Discharges and Nonconvulsive Seizures in Posterior Reversible Encephalopathy Syndrome (PRES).

IMPORTANCE: The pathophysiological mechanisms of Posterior Reversible Encephalopathy Syndrome (PRES) and related seizures remain poorly understood. The prevalence and clinical significance of nonconvulsive seizures (NCSz) and related epileptiform patterns during continuous electroencephalography monitoring (CEEG) in PRES have not been well described. OBJECTIVE: To report the prevalence, characteristics and risk factors for NCSz and related highly epileptiform patterns in patients with PRES, and to determine their relation to imaging abnormalities and outcome. DESIGN, SETTING AND PARTICIPANTS: From a prospective CEEG database, we retrospectively identified patients with PRES and reviewed their medical charts. Based on CEEG findings, we designed a retrospective cohort study comparing two groups defined based on the presence or the absence of NCSz and/or periodic discharges (PDs). MAIN OUTCOMES AND MEASURES: The prevalence and risk factors for PDs and NCSz, description of EEG and magnetic resonance imaging (MRI) abnormalities and functional outcome as measured by the Glasgow Outcome Scale (GOS) at hospital discharge. RESULTS: Among 37 eligible patients, 23 (62%) had PDs or NCSz. The presence of NCSz was associated with the presence of PDs (15/22 vs. 1/15; p = 0.0002). NCSz and PDs were usually either lateralized or bilateral independent and predominated in the posterior regions. No clinical features were associated with the occurrence of PDs or NCSz. Cortical restricted diffusion on MRI was more frequent in the PDs/NCSz group (17/23 vs. 1/14; p < 0.001). PDs/NCSz were associated with worse outcome, with 3 deaths vs. 0 in the no PDs/NCSz group and fewer cases with low disability (4 vs. 9 cases with GOS = 5, p < 0.04). CONCLUSIONS AND RELEVANCE: Our results reveal a high prevalence of NCSz and PDs in critically ill patients with PRES and an association with restricted diffusion and worse outcome, whether treating or preventing these EEG findings can improve outcome requires further research.

Time-dependent risk of seizures in critically ill patients on continuous electroencephalogram.

OBJECTIVE: Find the optimal continuous electroencephalographic (CEEG) monitoring duration for seizure detection in critically ill patients. METHODS: We analyzed prospective data from 665 consecutive CEEGs, including clinical factors and time-to-event emergence of electroencephalographic (EEG) findings over 72 hours. Clinical factors were selected using logistic regression. EEG risk factors were selected a priori. Clinical factors were used for baseline (pre-EEG) risk. EEG findings were used for the creation of a multistate survival model with 3 states (entry, EEG risk, and seizure). EEG risk state is defined by emergence of epileptiform patterns. RESULTS: The clinical variables of greatest predictive value were coma (31% had seizures; odds ratio [OR] = 1.8, p < 0.01) and history of seizures, either remotely or related to acute illness (34% had seizures; OR = 3.0, p < 0.001). If there were no epileptiform findings on EEG, the risk of seizures within 72 hours was between 9% (no clinical risk factors) and 36% (coma and history of seizures). If epileptiform findings developed, the seizure incidence was between 18% (no clinical risk factors) and 64% (coma and history of seizures). In the absence of epileptiform EEG abnormalities, the duration of monitoring needed for seizure risk of <5% was between 0.4 hours (for patients who are not comatose and had no prior seizure) and 16.4 hours (comatose and prior seizure). INTERPRETATION: The initial risk of seizures on CEEG is dependent on history of prior seizures and presence of coma. The risk of developing seizures on CEEG decays to <5% by 24 hours if no epileptiform EEG abnormalities emerge, independent of initial clinical risk factors. Ann Neurol 2017;82:177-185.

Cyclic seizures in critically ill patients: Clinical correlates, DC recordings and outcomes.

OBJECTIVE: To describe EEG and clinical correlates, DC recordings and prognostic significance of cyclic seizures (CS). METHODS: We reviewed our prospective continuous EEG database to identify patients with CS, controls with non-cyclic status epilepticus (SE) and controls without seizure matched for age and etiology. EEG was reviewed with DC settings. RESULTS: 39/260 (15%) patients with electrographic seizures presented with CS. These patients were older (62 vs. 54years; p=0.04) and more often had acute or progressive brain injury (77% vs. 52%; p=0.03) than patients with non-cyclic SE and had a lower level of consciousness, were more severely ill, than matched controls. CS almost always had focal onset, often from posterior regions. Patients with CS trended towards worse prognosis. When available (12 patients), DC recordings showed an infraslow cyclic oscillation of EEG baseline synchronized to the seizures in all cases. CONCLUSIONS: CS occur mostly in older patients with acute or progressive brain injury, are more likely to be associated with poor outcome than patients with other forms of nonconvulsive SE, and are accompanied by synchronous oscillations of the EEG baseline on DC recordings. SIGNIFICANCE: CS are a common form of non-convulsive status epilepticus in critically ill patients and provide further insights into the relationship between infraslow activity and seizures; further study on this relationship may shed light on the mechanisms of seizure initiation and termination.

The use and yield of continuous EEG in critically ill patients: A comparative study of three centers.

OBJECTIVE: Continuous EEG (cEEG) monitoring of critically ill patients has gained widespread use, but there is substantial reported variability in its use. We analyzed cEEG and antiseizure drug (ASD) usage at three high volume centers. METHODS: We utilized a multicenter cEEG database used daily as a clinical reporting tool in three tertiary care sites (Emory Hospital, Brigham and Women's Hospital and Yale - New Haven Hospital). We compared the cEEG usage patterns, seizure frequency, detection of rhythmic/periodic patterns (RPP), and ASD use between the sites. RESULTS: 5792 cEEG sessions were analyzed. Indication for cEEG monitoring and recording duration were similar between the sites. Seizures detection rate was nearly identical between the three sites, ranging between 12.3% and 13.6%. Median time to first seizure and detection rate of RPPs were similar. There were significant differences in doses of levetiracetam, valproic acid, and lacosamide used between the three sites. CONCLUSIONS: There was remarkable uniformity in seizure detection rates within three high volume centers. In contrast, dose of ASD used frequently differed between the three sites. SIGNIFICANCE: These large volume data are in line with recent guidelines regarding cEEG use. Difference in ASD use suggests discrepancies in how cEEG results influence patient management.

Clinical Correlates and Prognostic Significance of Lateralized Periodic Discharges in Patients Without Acute or Progressive Brain Injury: A Case-Control Study.

PURPOSE: Lateralized periodic discharges (LPDs, also known as periodic lateralized epileptiform discharges) in conjunction with acute brain injuries are known to be associated with worse prognosis but little is known about their importance in absence of such acute injuries. We studied the clinical correlates and outcome of patients with LPDs in the absence of acute or progressive brain injury. METHODS: This is a case-control study of 74 patients with no acute brain injury undergoing continuous EEG monitoring, half with LPDs and half without, matched for age and etiology of remote brain injury, if any, or history of epilepsy. RESULTS: Lateralized periodic discharges were found in 145/1785 (8.1%) of subjects; 37/145 (26%) had no radiologic evidence of acute or progressive brain injury. Those with LPDs were more likely to have abnormal consciousness (86% vs. 57%; P = 0.005), seizures (70% vs. 24%; P = 0.0002), and functional decline (62% vs. 27%; P = 0.005), and were less likely to be discharged home (24% vs. 62%; P = 0.002). On multivariate analysis, LPDs and status epilepticus were associated with abnormal consciousness (P = 0.009; odds ratio = 5.2, 95% CI = 1.60-20.00 and P = 0.017; odds ratio = 5.0, 95% CI = 1.4-21.4); and LPDs were independently associated with functional decline (P = 0.001; odds ratio = 4.8, 95% CI = 1.6-15.4) and lower likelihood of being discharged home (P = 0.009; odds ratio = 0.2, 95% CI = 0.04-0.6). CONCLUSIONS: Despite absence of acute or progressive brain injury, LPDs were independently associated with abnormal consciousness and worse outcome at hospital discharge.

Prognostication of post-cardiac arrest coma: early clinical and electroencephalographic predictors of outcome.

PURPOSE: To determine the temporal evolution, clinical correlates, and prognostic significance of electroencephalographic (EEG) patterns in post-cardiac arrest comatose patients treated with hypothermia. METHODS: Prospective cohort study of consecutive post-anoxic patients receiving hypothermia and continuous EEG monitoring between May 2011 and June 2014 (n = 100). In addition to clinical variables, 5-min EEG clips at 6, 12, 24, 48, and 72 h after return of spontaneous circulation (ROSC) were reviewed. EEG background was classified according to the American Clinical Neurophysiological Society critical care EEG terminology. Clinical outcome at discharge was dichotomized as good [Glasgow outcome scale (GOS) 4-5, low to moderate disability] vs. poor (GOS 1-3, severe disability to death). RESULTS: Non-ventricular fibrillation/tachycardia arrest, longer time to ROSC, absence of brainstem reflexes, extensor or no motor response, lower pH, higher lactate, hypotension requiring >2 vasopressors, and absence of reactivity on EEG were all associated with poor outcome (all p values ≤ 0.01). Suppression-burst at any time indicated a poor prognosis, with a 0% false positive rate (FPR) [95% confidence interval (CI) 0-10%]. All patients (54/54) with suppression-burst or a low voltage (<20 µV) EEG at 24 h had a poor outcome, with an FPR of 0% [95% CI 0-8%]. Normal background voltage ≥ 20 µV without epileptiform discharges at any time interval carried a positive predictive value >70% for good outcome. CONCLUSIONS: Suppression-burst or a low voltage at 24 h after ROSC was not compatible with good outcome in this series. Normal background voltage without epileptiform discharges predicted a good outcome.

Brief potentially ictal rhythmic discharges in critically ill adults.

IMPORTANCE: Brief potentially ictal rhythmic discharges, termed B(I)RDs, have been described mainly in neonates, and their significance in adults remains unclear. OBJECTIVE: To describe the incidence of B(I)RDs in critically ill patients and investigate their association with seizures and outcome. DESIGN, SETTING, AND PARTICIPANTS: We reviewed the records of prospectively identified patients with B(I)RDs and patients serving as controls matched for age (±5 years) and primary diagnosis. MAIN OUTCOMES AND MEASURES: The prevalence of seizures during continuous electroencephalography and functional outcome, as measured by the Glasgow Outcome Scale, were determined. RESULTS: We identified B(I)RDs in 20 patients (2%). The pattern most often consisted of very brief (1-3 seconds) runs of sharply contoured theta activity without obvious evolution. All patients with B(I)RDs had cerebral injury, and in cases with a single focal lesion (11 [55%]), B(I)RDs were localized in the same region in all but 2 cases (18%). Patients with B(I)RDs were more likely to have seizures during continuous electroencephalography than were patients without B(I)RDs (15 of 20 [75%] vs 10 of 40 [25%]; P < .001), and 9 patients with B(I)RDs (60%) had only subclinical seizures. Brief potentially ictal rhythmic discharges were identified before seizures in all but 1 case (93%) and ceased in all 12 cases (80%) in which seizures were controlled. Patients with B(I)RDs tended to have a worse outcome than controls (16 [80%] vs 25 [63%]); however, this finding was not statistically significant. CONCLUSIONS AND RELEVANCE: Brief potentially ictal rhythmic discharges in critically ill patients are associated with a high prevalence (75%) of electrographic seizures and might serve as an early predictor of seizures during subsequent monitoring. A larger prospective study is needed to better understand their clinical and prognostic significance.

Similarity of lateralized rhythmic delta activity to periodic lateralized epileptiform discharges in critically ill patients.

IMPORTANCE: The increasing use of continuous electroencephalography (EEG) monitoring in the intensive care unit has led to recognition of new EEG patterns that are of unclear or unknown significance. OBJECTIVE: To describe an EEG pattern, lateralized rhythmic delta activity (LRDA), encountered in critically ill subjects and determine its clinical significance in this setting. DESIGN, SETTING, AND PARTICIPANTS Retrospective review at an academic medical center of EEG recordings, medical records, and imaging studies of critically ill patients with LRDA and comparison with subjects with lateralized periodic discharges (also known as periodic lateralized epileptiform discharges), subjects with focal nonrhythmic slowing, and controls. INTERVENTION: Electroencephalography or continuous electroencephalography. MAIN OUTCOMES AND MEASURES: Cross-sectional prevalence of lateralized rhythmic delta activity; EEG characteristics; etiology, clinical, and radiological correlates; and risk of early seizures. RESULTS: We identified LRDA in 4.7%of acutely ill subjects undergoing EEG or continuous EEG monitoring. It was often associated with other focal EEG abnormalities, including lateralized periodic discharges in 44%of cases. The most common conditions associated with LRDA were intracranial hemorrhage and subarachnoid hemorrhage. Lateralized rhythmic delta activity was an independent predictor of acute seizures, with 63%of subjects having seizures during their acute illness, a proportion similar to subjects with lateralized periodic discharges (57%) and significantly higher than associated with focal nonrhythmic slowing (20%) or in control subjects (16%). Most patients (80%-90%) in the LRDA and lateralized periodic discharges groups who had seizures while undergoing continuous EEG monitoring had only nonconvulsive seizures, whereas this was the case for only 17%of patients in the other groups. Lateralized rhythmic delta activity and lateralized periodic discharges were both associated with lesions involving the cortex or juxtacortical white matter. CONCLUSIONS AND RELEVANCE: Lateralized rhythmic delta activity in critically ill patients has a similar clinical significance as lateralized periodic discharges. It reflects the presence of a focal lesion and is associated with a high risk of acute seizures, especially nonconvulsive.